PROJECT SUMMARY/ABSTRACT Alzheimer?s disease (AD) is the most common and severe age-associated neurodegenerative dementia of our times for which there is no cure. Synaptic dysfunction induced by the dysfunctional targeting toxic oligomers of both Ab and Tau (the two hallmark amyloids in AD) is recognized as one of the earliest events in AD, driving initial cognitive decline and clinical manifestation. Preventing such oligomer disrupting action on synapses would thus be an effective and comprehensive therapy for AD, blocking the combined driving toxicity of both A? and tau. However, a strategy to achieve this important goal remains elusive. In the present project we wish to address this critical knowledge gap by testing the hypothesis that activation of calcineurin (CN) mediates the synergistic effect of A? and tau oligomers on synapses. CN is a CNS-abundant phosphatase critically involved in synaptic function and memory formation. CN activity is abnormally increased the brain of AD patients as well as tg mouse models of AD, and inhibition of CN with FK506 (an FDA-approved immunosuppressant drug) protects synapses from A? oligomers and restores memory in transgenic AD mouse models. Most notably, we showed that the incidence of AD in solid organ transplant recipients chronically treated with FK506 is dramatically reduced as compared to the general population. This is highly significant in light of recent evidence showing that overexpression of hTau induces elevated CN in the CNS, and that tau oligomers induce synaptic deficits and memory dysfunction in synergy with A? oligomers, strongly suggesting that the two species impinge upon a common molecular target mediating their combined key role in AD onset and clinical progression. We propose that such common target is CN and that CN inhibition is an effective approach to block the combined toxicity of tau and A? oligomers that drive AD. In the present project will employ in vitro, ex vivo and in vivo models and autopsy human brain specimens to mechanistically test our hypothesis by characterizing the role of CN in mediating the disruptive effects of tau oligomers (Aim 1) and by establishing CN as the common target mediating the combined, synergistic impact of tau and Ab oligomers on synaptic and memory function (Aim 2). At the completion of the proposed studies we will have documented a previously unappreciated role of CN as the point of molecular convergence of the toxic oligomers of the two amyloid proteins that hallmark AD neuropathology, tau and A?, and illustrated the beneficial effects of FK506 in preventing their combined toxicity. Given the translational value of FK506 (an FDA-approved drug) this discovery will have a substantial impact in the field by promoting the development of an innovative treatment concept for AD centered on simultaneous blockade of tau and A? toxic species, a strategy expected to be effective in humans as suggested by the resilience to AD of transplanted patients chronically treated with FK506.